Astrocyte‐produced leukemia inhibitory factor expands the neural stem/progenitor pool following perinatal hypoxia–ischemia

Abstract

Brain injuries, such as cerebral hypoxia-ischemia (H–I), induce a regenerative response from the neural stem/progenitors (NSPs) of the subventricular zone (SVZ); however, the mechanisms that regulate this expansion have not yet been fully elucidated. The Notch-DSL signaling pathway is considered essential for the maintenance of neural stem cells, but it is not known if it is necessary for the expansion of the NSPs subsequent to perinatal H–I injury. Therefore, the aim of this study was to investigate whether this pathway contributes to NSP expansion in the SVZ after H–I and if so, to establish whether this pathway is directly induced by H–I or regulated by paracrine factors. Here we report that Notch1 receptor induction and one of its ligands, Delta-like 1 precedes NSP expansion after perinatal hypoxia-ischemia in P6 rat pups and that this increase occurs specifically in the most medial cell layers of the SVZ where the stem cells reside. Pharmacologically inhibiting Notch signaling in vivo diminished NSP expansion. With an in vitro model of H–I, Notch1 was not induced directly by hypoxia, but was stimulated by soluble factors, specifically leukemia inhibitory factor, produced by astrocytes within the SVZ. These data confirm the importance both of the Notch-DSL signaling pathway in the expansion of NSPs after H–I and in the role of the support cells in their niche. They further support the body of evidence that indicates that leukemia inhibitory factor is a key injury induced cytokine that is stimulating the regenerative response of the NSPs.

Application of bio-orthogonal proteome labeling to cell transplantation and heterochronic parabiosis

“…LIF-1 is well known to activate the Jak/Stat pathway, which has been shown to reduce symmetric division of myogenic precursors, which would possibly signify return to quiescence, and to promote fusion into myotubes (at the other end of myogenic lineage) 42 . But LIF-1 also activates the MAPK signaling, which can induce the Notch activating ligands Delta and Jagged, promoting myogenic proliferation 43 , 44 .…”

The role of the leukemia inhibitory factor receptor in neuroprotective signaling

“…NSC populations upregulate LIF mRNA following stimulation with interferon γ, which is produced by T lymphocytes and natural killer cells after stroke. This secretion of LIF promotes brain repair by acting on neural cells and by triggering proliferation of other NSCs (Felling, Covey, Wolujewicz, Batish, & Levison, 2016; Laterza et al, 2013; Yilmaz, Arumugam, Stokes, & Granger, 2006). Neurons also increase expression of LIF in response to injury.…”

Pediatric brain repair from endogenous neural stem cells of the subventricular zone

“…In their 2006 paper, Felling et al (50) provided evidence implicating Notch signaling in the expansion of the neural progenitor (NP) pool. More recently, Felling et al (51) used an in vitro model for H-I, hypoglycemia, and hypoxia (H-H), and showed that H-H itself is not sufficient to induce Notch-1, but that H-H induces astrocytes to produce leukemia inhibitory factor, which in turn increases Notch1 expression in the neural stem/ progenitors (NSPs). There is a controversy as to whether neonatal H-I increases the proportion of bona fide neural stem cells vs. progenitors.…”

“…Notch receptors are transmembrane proteins that are activated by membrane bound Delta and Jagged ligands and they are expressed by the stem cells and progenitors in the SVZ (94). Studies by Felling et al (50,51) showed that H-I increases the expression of Notch1 as well as one of its ligands, Delta-like 1, that results in increased expression of the downstream effectors, Hes1 and Hes5, within the NSPs of the SVZ. They further showed that pharmacologically decreasing Notch1 activity during the acute recovery period in vivo abrogated the increase in NSPs seen after neonatal H-I.…”

“…Studies profiling the cytokine induction after perinatal brain injuries have shown that LIF is significantly increased within 1 day after neonatal and pediatric brain injury and thus precedes the increase in NSCs and progenitors (108). Astrocytes are activated by central nervous system injury and a single-molecule fluorescence in situ hybridization study for LIF and for GFAP showed that astrocytes are the major LIF expressing cells after neonatal H-I (51). The LIF that is secreted by the astrocytes may be essential for NP expansion after neonatal H-I (25).…”